Prostate cancer (PC) is the most frequently diagnosed male cancer and the second leading cause of cancer-associated mortality in Western countries. PC is typically diagnosed on the basis of increased serum prostate specific antigen (PSA) levels followed by histopathological inspection of needle biopsies. The use of PSA for PC detection, however, is associated with considerable false positive rates and does not distinguish well between indolent and aggressive tumours. During the past decades, increased use of PSA testing and PSA based screening has resulted in higher incidences as well as down-staging of the disease. Combined with the lack of accurate prognostic tools, this has caused substantial overdiagnosis and overtreatment of clinically insignificant PCs. Thus, although some PC patients benefit from radical prostatectomy, conservative management (active surveillance or watchful waiting) is the preferred option for some patients with low or intermediate risk PC. Up to a third of patients undergoing radical prostatectomy suffers disease recurrence (biochemical relapse) within 5-10 years and eventually develops distant metastases. Progression to metastatic disease can be delayed by androgen deprivation therapy, but most tumours become resistant within two years and advance to castrate-refractory prostate cancer (CRPC) associated with high morbidity and mortality.
Methylation of DNA is a mechanism for changing the base sequence of DNA without altering its coding function. DNA methylation is a heritable, reversible and epigenetic change. DNA methylation harbours the potential to alter gene expression which in turn affects developmental and genetic processes.
CpG-rich sequences are known as CpG islands. CpG islands are distributed across the human genome and often span the promoter region as well as the first 5′ exon of protein coding genes. Methylation of individual promoter region CpG islands usually turns off transcription by recruiting histone deacetylases, which supports the formation of inactive chromatin (Humphrey P A et al.: Mod Pathol 2004; 17: 292-306). CpG islands are typically between 0.2 to about 1 kb in length and are located upstream of many housekeeping and tissue-specific genes, but may also extend into gene coding regions. Therefore, it is the methylation of cytosine residues within CpG islands in somatic tissues, which is believed to affect gene function by altering transcription (Cedar, Cell 53:3-4, 1988).